Many disorders and conditions of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of disorders and conditions which originate in the central nervous system. A number of pharmacological and genetic experiments involving receptors for serotonin strongly implicate the 5-HT2C receptor subtype in the regulation of food intake (see e. g., Obes. Res. 1995, 3, Suppl. 4, 449S–462S, Diabetes, Obesity and Metabolism 1999, 1, 207–214, and Drugs Future 2001, 26, 383–393). The 5-HT2C receptor subtype is transcribed and expressed in hypothalamic structures associated with appetite regulation. It has been demonstrated that the 5-HT2C receptor agonist m-chlorophenyl-piperazine (mCPP), which has some preference for the 5-HT2C receptor, reduces food intake in mice that express the normal 5-HT2C receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT2C receptor (Nature 1995, 374, 542–546). In a recent clinical study, a slight but sustained reduction in body weight was obtained after 2 weeks of treatment with mCPP in obese subjects (Psychopharmacology 1997, 133, 309–312). Recently, a series of pyrrolo[3,2,1-ij]quinoline derivatives was identified to be 5-HT2C receptor agonists having selectivity over the 5-HT2A receptor (Isaac M., et al., Bioorg. Med. Chem. Lett. 2000, 10, 919–921). The compounds are said to offer a novel approach to the treatment of obesity and epilepsy.
Body weight reduction has also been reported from clinical studies with other “serotonergic” agents (see e.g. IDrugs 1998, 1, 456–470). For example, the 5-HT reuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptake inhibitor dexfenfluramine have exhibited weight reduction in controlled studies. However, currently available drugs that increase serotonergic transmission appear to have only a moderate and, in some cases, transient effects on the body weight.
The 5-HT2C receptor subtype has also been suggested to be involved in CNS disorders such as depression and anxiety (Exp. Opin. Invest. Drugs 1998, 7, 1587–1599; IDrugs, 1999, 2, 109–120).
The 5-HT2C receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (IDrugs, 1999, 2, 109–120).
Compounds which have a selective effect on the 5-HT2C receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above. Of course, selectivity also reduces the potential for adverse effects mediated by other serotonin receptors.